|[Frontiers in Bioscience 2, d271-282, June 1, 1997]|
THE ROLE OF LANGERHANS ISLETS IN PANCREATIC DUCTAL ADENOCARCINOMA|
Parviz M. Pour
The UNMC/Eppley Cancer Center, University of Nebraska
Medical Center, Omaha, NE
Received 5/6/97 Accepted 6/2/97
The existence of an endocrineexocrine interaction
is convincingly demonstrated in some pancreatic diseases, especially
in pancreatic cancer. In the hamster pancreatic cancer model,
which in morphological, molecular biological, clinical, and immunological
aspects mimics the human disease (29,34-43), the participation
of endocrine cells in the development of exocrine cancer begins
very early during carcinogenesis. In this model, various numbers
and types of islet cells are found within the hyperplastic, preneoplastic
and neoplastic cells forming ductal and ductular structures (Fig.
2; 29,34,37,44-48). These endocrine cells are primarily located
in the basal aspect of the glands. However, they can be found
scattered at different levels of the multilayered epithelium (Fig. 3).
The pattern of their distribution within the malignant epithelium
and the presence of exfoliated endocrine cells and material immunoreactive
with antiinsulin in the lumen of these glands indicates
that, like malignant ductal/ ductular cells, the endocrine cells
are renewed and shed. This phenomenon could explain the higher
level of islet hormones which exist in the pancreatic juice of
animals with pancreatic cancer than in normal control hamsters
(45). Another interesting phenomenon in this pancreatic cancer
model is an exaggerated formation of periinsular and intrainsular
ductules, which otherwise are rarely seen in control animals
(29,34,46-48). In fact, these intrainsular ductular structures
are the earliest lesions induced, whereas alterations of ductal
and ductular epithelium occur later. Depending on the dose of
the carcinogen, these periinsular and intrainsular ductules gradually
become visible in some or many islets. Within the islets, they
expand, ramify (Figs. 4,5), and ultimately form either microcystic
structures resembling human serous cystadenomas (Fig. 6) or become
increasingly hyperplastic and atypical and finally transform to
malignant structures which are indistinguishable from similarly
altered ductal cells (Figs. 7,8). These malignant intrainsular
and periinsular ductules gradually replace the islets and leave
only a small group or single islet cells which can best be demonstrated
immunohistochemically (Fig. 9). Similar, randomly scattered islet
cells can also be found within the invasive well-differentiated
cancers. With decreasing differentiation of cancer cells, the
numbers of endocrine cells decrease, but they may still be found
in some invasive and metastasizing tumors (45). These findings
indicate that certain cells, within or around islets, possibly
correspond to the "Trübe Zelle" (49), "inselpotente
Zelle" (50), "nesidioblasts" (51), "immature
b-cells" (52), or "islet precursor cells,"
which have been recognized in the pancreas of many species, including
the hamster (47), and represent tumor progenitor cells. These
pluripotent cells, which obviously are also distributed randomly
along the pancreatic ductal system, seem to be particularly responsive
to carcinogenic insult. Within the islets, where they presumably
present a source of new islet cells, they lose their ability to
differentiate into islet cells and resume the undifferentiated,
ductlike phenotype and undergo malignant transformation
the same way as do the corresponding cells within the ductal/ductular
epithelium. As discussed below, the expression of tumorassociated
carbohydrate antigens, such as CA 19-9, DU-PAN-2 and TAG-72, by
islet cells in the immediate vicinity of pancreatic cancer (53),
is in line with the differentiation failure of these precursor
cells. It is, nevertheless, ironic to see that endocrine tissue
"gives rise" to exocrine pancreatic cancer.
Fig. 2. Early stage in the development of pancreatic cancer. Cells immunoreactive for somatostatin (red) are seen within the hyperplastic epithelium of a ductule. X 210.
Fig. 3. Somatostatin
(red) and insulin immunoreactive cells (brown) in a pancreatic
cancer. Nothe the distribution of the endocrine cells in all layers
of the malignant epithelium. X 210. (From reference 53, with permission).
Fig 4. Distended and ramified intrainsular ductules in a pancreas of a hamster treated with the pancreatic carcinogen, BOP. This was the only microscopic finding in the pancreas of this animal. H&E, X 210.
Fig. 5. Ramified and distended intrainsular ductules at early stages of pancreatic carcinogenesis. There were no changes in the exocrine pancreas. H&E, X 120.
Fig. 6. Convergence of
cystic intrainsular ductules of neighboring islets forming a pattern
resembling microcystic adenoma. Remnants of islet cells are marked
by arrows. H&E, X 75.
Fig. 7. Proliferation and distention of intrainsular ductules with a hyperplastic epithelium. H&E. X 120.
Fig.8. Malignant alterations of one segment of intrainsular ductules with invasion of the surrounding tissue. H&E, X 120. (From reference 29, with permission).
Fig . 9. A moderately - differentiated pancreatic adenocarcinoma containing cells immunoreactive with chromogranin A (red) X 210.